Subarachnoid fluid management method and system with varying rates

ABSTRACT

A CSF management method for use with a patient forms a closed loop CSF circuit between two points on the patient&#39;s body. The CSF circuit has a therapeutic inlet to receive a therapeutic material (e.g. a drug), and a pump having a pump outlet to direct CSF along the CSF circuit. The method controls the pump to direct CSF from the pump outlet at a CSF rate that is different from the natural flow rate (i.e., the natural CSF flow rate). The therapeutic material is added to the CSF via the therapeutic input at a therapeutic rate. The CSF rate is different than the therapeutic rate and/or may be greater than the therapeutic rate. Alternative methods may control a bolus drug infusion to localize the application to a target region.

PRIORITY

This patent application claims priority from provisional U.S. patentapplication No. 63/084,996, filed Sep. 29, 2020, entitled, “SUBARACHNOIDFLUID MANAGEMENT SYSTEM,” and naming Gianna Riccardi, William Siopes,Jr., Marcie Glicksman, Anthony DePasqua, Kevin Kalish, and Joshua Voseas inventors, the disclosure of which is incorporated herein, in itsentirety, by reference.

This patent application also claims priority from provisional U.S.patent application No. 63/117,975, filed Nov. 24, 2020, entitled,“SUBARACHNOID FLUID MANAGEMENT SYSTEM,” and naming Gianna Riccardi,William Siopes, Jr., Marcie Glicksman, Anthony DePasqua, Kevin Kalish,and Joshua Vose as inventors, the disclosure of which is incorporatedherein, in its entirety, by reference.

GOVERNMENT RIGHTS

None

FIELD

Illustrative embodiments generally relate to medical devices and methodsand, more particularly, illustrative embodiments relate to devices andmethods for managing subarachnoid fluid, such as cerebrospinal fluid(“CSF”), and/or drug delivery that may be used to treatneurodegenerative disorders.

BACKGROUND

When delivering a drug intrathecally, it is difficult to ensure that thedelivered dosage reaches the target anatomy (e.g., part of the braincorrelating to a specific disease, such as the cortical versussubcortical). It also is difficult to verify the actual dosage deliveredto the target anatomy, as well as control, in real time, theconcentration of the drug in the fluid surrounding the target anatomy.

SUMMARY OF VARIOUS EMBODIMENTS

In accordance with one embodiment of the invention, a CSF managementmethod for use with a patient forms a closed loop CSF circuit betweentwo points on the patient's body. The CSF circuit has a therapeuticinlet to receive a therapeutic material (e.g. a drug), and a pump havinga pump outlet to direct CSF along the CSF circuit. The method controlsthe pump to direct CSF from the pump outlet at a CSF rate that isdifferent from the natural flow rate (i.e., the natural CSF flow rate).The therapeutic material is added to the CSF via the therapeutic inputat a therapeutic rate. The CSF rate is different than the therapeuticrate and/or may be greater than the therapeutic rate.

The CSF rate may be a constant rate, or a rate that varies over time.The CSF circuit may be configured so that the CSF simultaneously flowsat different rates at two different locations of the CSF circuit.Moreover, the CSF circuit preferably accesses one or more CSF-containingcompartments within patient anatomy, such as one or more of the lateralventricles, the lumbar thecal sac, the third ventricle, the fourthventricle, and the cisterna magna.

The CSF circuit may have a port into the patient (e.g., a Luer activatedvalve or other valve). In that case, some embodiments of the CSF circuithave a fluid channel (e.g., a catheter) removably coupled with the portand the pump. To improve performance, the fluid channel also may have aflow sensor, a pressure sensor, or both a flow sensor and a pressuresensor. In addition or alternatively, the fluid channel may have acontroller (e.g., an EEPROM) in communication with the pump configuredto track the total number of uses of the fluid channel.

In accordance with another embodiment, a CSF management method for usewith a patient forms a CSF circuit to control flow of CSF in the body,adds a therapeutic material to the patient's CSF via the CSF circuit,and directs the therapeutic material (e.g., a drug), via the CSF, towarda prescribed portion of the body. Favorably, the method varies the flowof the CSF in the CSF circuit to localize the CSF at the prescribedportion of the body.

To localize, some embodiments may oscillate the flow of CSF within theCSF circuit for a prescribed time and at a prescribed frequency. To thatend, the CSF circuit may have a therapeutic delivery pump and a flowcontrol pump. The therapeutic delivery pump may be directly in line witha reservoir of therapeutic material. Some embodiments may vary the CSFflow rate within the CSF circuit at two or more flow rates at two ormore different times. As another option, the CSF circuit may producepulsatile CSF flow.

The CSF circuit preferably is a closed loop channel in communicationwith the lower abdomen of a human being. As with other embodiments, theCSF circuit may access one or more CSF-containing compartments withpatient anatomy, including one or more of the lateral ventricles, thelumbar thecal sac, the third ventricle, the fourth ventricle, and thecisterna magna.

Some embodiments mix, in a mixing chamber, the therapeutic material andthe CSF and/or display a control panel interface configured to controlone or both of CSF flow rate and an oscillation frequency. The methodmay track the progression of the therapeutic material as it flowsthrough the CSF circuit. In that case, the method may vary by reducingthe CSF flow rate after the therapeutic material contacts the prescribedportion of the body. When imaging the location of the CSF and/or thetherapeutic material, the method may localize as a function of thelocation of the CSF and/or therapeutic material.

As with other embodiments, this embodiment of the CSF circuit may have aport into the patient (e.g., a Luer activated valve or other valve). Inthat case, some embodiments of the CSF circuit have a fluid channel(e.g., a catheter or a needle) removably coupled with the port and thepump. To improve performance, the fluid channel also may have a flowsensor, a pressure sensor, or both a flow sensor and a pressure sensor.In addition or alternatively, the fluid channel may have a controller(e.g., using an EEPROM) in communication with the pump configured totrack the total number of uses, shelf life, or sterilization date of thefluid channel.

Illustrative embodiments add a bolus of therapeutic material, such as afull dose in less than 60 seconds.

In accordance with other embodiments, a CSF fluid conduit (e.g., acatheter) directs CSF flow to or from a patient having an exterior portin fluid communication with that patient's subarachnoid space. The CSFfluid conduit is compatible with a CSF circuit having a pump forcontrolling CSF fluid flow. Accordingly, to those ends, the CSF fluidconduit has a body forming a fluid traversing bore. The body, which hasfirst and second ends in fluid communication with the bore, areremovably couplable between the exterior port of the patient and thepump. The bore is in fluid communication with both the exterior port andpump when removably coupled therebetween. Additionally, the body isconfigured to form a closed loop CSF channel when removably coupledbetween the pump and the interface, and the CSF channel and bore are influid communication with the patient's subarachnoid space when the bodyis removably coupled. The CSF fluid conduit also has a flow sensorconfigured to detect flow through the bore of the body, a pressuresensor configured to detect pressure within the bore of the body, and acontroller having a communication channel with the pump. The controllerhas a usage meter configured to track use of the CSF fluid conduit.

The first end of the body preferably is configured to removably couplewith the exterior port of the patient via a removable coupling, such asa conventional ANSI standard Luer lock or needle. In a correspondingmanner, the second end of the body may be configured to removably couplewith the pump.

The removable coupling can be direct or indirect. For example, it may bean indirect connection and, as such, the fluid circuit may have at leastone additional component between the first end and the exterior port ofthe patient. The at least one additional component thus is between thesecond port and the pump. Of course, related embodiments may removablycouple by directly removably coupling with the specific component.

To manage use of the conduit, the controller may be configured toproduce indicia indicating at least one use of the CSF fluid conduit.Moreover, when the bore is configured to receive a therapeutic materialmixed with CSF, the controller may be configured to control fluid flowas a function of the therapeutic material. The flow sensor may beconfigured to detect a variety of items, such as the rate of fluid flowthrough the bore and/or the total volume of fluid through the bore.Further, the controller may be configured to permit a maximum time touse the CSF fluid conduit. The conduit also may have a programmablelogic element configured to be programmed to sense or control use of theCSF fluid conduit.

Illustrative embodiments of the invention are implemented as a computerprogram product having a computer usable medium with computer readableprogram code thereon. The computer readable code may be read andutilized by a computer system in accordance with conventional processes.

BRIEF DESCRIPTION OF THE DRAWINGS

Those skilled in the art should more fully appreciate advantages ofvarious embodiments of the invention from the following “Description ofIllustrative Embodiments,” discussed with reference to the drawingssummarized immediately below.

FIG. 1A schematically shows a cerebrospinal fluid circuit that may beused with illustrative embodiments of the invention.

FIG. 1B schematically shows an external catheter configured inaccordance with illustrative embodiments.

FIG. 1C shows a high level surgical flow process in accordance withillustrative embodiments of the invention.

FIG. 2 schematically shows a two pump circuit with drug fed into pumpthrough separate fluid line in accordance with illustrative embodiments.

FIG. 3 schematically shows a two pump circuit with drug introduceddirectly into fluid line

FIG. 4A schematically shows a flow control valve circuit that may beused with illustrative embodiments.

FIG. 4B schematically shows a syringe pump dosing circuit with a drugintroduced directly into the fluid line configured and usable withillustrative embodiments.

FIG. 5 schematically shows a two-pump circuit with a mixing chamber inaccordance with illustrative embodiments.

FIG. 6 schematically shows a flow control valve with a mixing chamber inaccordance with other embodiments.

FIGS. 7 and 8 schematically show two different user interfaces inaccordance with illustrative embodiments.

FIG. 9 shows a process of localizing drug delivery to a target area ofthe brain in accordance with illustrative embodiments.

FIG. 10 schematically shows directing flow from lumbar to ventricle inaccordance with illustrative embodiments.

FIG. 11 schematically shows directing flow from ventricle to lumbar inaccordance with illustrative embodiments.

FIG. 12 schematically shows directing flow from lumbar to ventricle witha pulsatile pattern in accordance with illustrative embodiments.

FIGS. 13A and 13B schematically show bidirectional pump circuits thatenable flow in two opposite directions (FIG. 13B between right and leftventricles in the brain) in accordance with illustrative embodiments.

FIG. 14 schematically shows another system interface in accordance withillustrative embodiments.

FIG. 15 shows a process of manually programming drug delivery inaccordance with illustrative embodiments.

FIGS. 16A, 16B, and 16C detail an example of illustrative embodiments ofthe invention.

FIGS. 17A, 17B, and 17C detail another example of illustrativeembodiments of the invention.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

In illustrative embodiments, a system controllably applies a therapeuticmaterial, such as a drug (e.g., methotrexate, a chemotherapy andimmunosuppressive drug) to a specific anatomical location within thesubarachnoid space or other area. The therapeutic material, which alsomay be referred to herein as a “drug,” may be applied in a single largevolume as a bolus, or dosed gradually over a longer time. To that end,the system has a controller or control system that manages distributionof the therapeutic material within a CSF circuit through whichcerebrospinal fluid (“CSF”) flows. Specifically, among other things, thecontroller (or “control system”) manages pumps, valves, catheters,and/or other structure(s) to control fluid flow, flow direction, andfrequencies of certain periodic flows of bodily fluids (e.g., CSF), toprovide a more localized and efficient therapeutic application to apatient.

Preferred embodiments enable the therapeutic material to penetrate theblood-brain barrier by either selecting appropriate CSF and therapeuticmaterial flow rates, and/or controlling CSF flow to maintain a bolus ofthe therapeutic material within CSF at/near a desired location in theCSF circuit. Consequently, using various embodiments, medicalpractitioners can be more comfortable applying the appropriateapplication of the therapeutic in the patient, while reducing toxicityand, in some cases, reducing the need for larger volumes of thetherapeutic. Details of illustrative embodiments are discussed below.

Many neurodegenerative diseases have been tied to the accumulation ofbiomolecules (e.g., toxic proteins) contained in cerebrospinal fluid(CSF) or other fluids (e.g., interstitial fluid) within the subarachnoidspace (SAS) of a mammalian subject. Problematically, these (e.g., toxic)biomolecules may be secreted and then transported by the CSF to othercells in the body, which process may occur over the span of years. Forexample, dipeptide repeat proteins (DPRs) and/or TDP-43 have beenimplicated in neuronal death in the pathology of amyotrophic lateralsclerosis (ALS, or Lou Gehrig's disease), Alzheimer disease (AD),frontotemporal degeneration (FTD), Parkinson's disease (PD),Huntington's disease (HD), and progressive supranuclear palsy (PSP), toname just a few. Hence, research has focused primarily on the removal ofharmful DPRs. Techniques for removing DPRs and/or TDP-43 have included:shunting CSF from the CSF space, diluting the CSF (e.g., with anartificial fluid), administering a drug into the CSF, conditioning theCSF, and/or manipulating CSF flow.

Recent breakthrough techniques for handling this problem includeameliorating the CSF, and treating a neurological disorder by removingor degrading a specific (toxic) protein.

Amelioration, as used in various embodiments, involves systems andmethods for ameliorating a fluid in the subarachnoid space (SAS) (e.g.,a cerebrospinal fluid (CSF), an interstitial fluid (ISF), blood, and thelike) of a mammalian subject, unless otherwise particularlydistinguished (e.g., referred to as solely CSF). Representative systemsmay be completely or partially implanted within the body of themammalian subject (discussed below). Within the body, the systems and/orcomponents thereof may also be completely or partially implanted withinthe SAS and exposed to the exterior via a port 16 (e.g., a medical valvethat provides selective access to the interior system components). Thesesystems execute processes that may occur entirely in-vivo, or some stepsthat occur extracorporeally. Illustrative embodiments ameliorate with aCSF circuit, discussed below.

Amelioration, for the purpose of illustration, may include changing thephysical parameters of the fluid, as well as digestion, removal,immobilization, reduction, and/or alteration, to become more acceptableand/or inactivation of certain entities, including: target molecules,proteins, agglomerations, viruses, bacteria, cells, couples, enzymes,antibodies, substances, and/or any combination thereof. For example, insome embodiments and applications, amelioration may refer to removingtoxic proteins from or conditioning one or more of the blood,interstitial fluid, or glymph contained therein, or other fluid, as wellas the impact that this removal has on treating diseases or conditionsthat affect various bodily functions, (i.e., improving the clinicalcondition of the patient). Moreover, amelioration may be performed byany one of: digestion, enzymatic digestion, filtration, size filtration,tangential flow filtering, countercurrent cascade ultrafiltration,centrifugation, separation, magnetic separation (including withnanoparticles and the like), electrophysical separation (performed bymeans of one or more of enzymes, antibodies, nanobodies, molecularimprinted polymers, ligand-receptor complexes, and other charge and/orbioaffinity interactions), photonic methods (includingfluorescence-activated cell sorting (FACS), ultraviolet (UV)sterilization, and/or optical tweezers), photo-acoustical interactions,chemical treatments, thermal methods, and combinations thereof.Advantageously, various embodiments or implementations of the presentinvention may reduce levels of toxicity and, after reduced, facilitatemaintaining the reduced levels over time.

The extent of amelioration, as reflected by the concentration of thetarget biomolecules, may be detected through a variety of means. Theseinclude optical techniques (e.g., Raman, coherent Stokes, andanti-Stokes Raman spectroscopy; surface enhanced Raman spectroscopy;diamond nitrogen vacancy magnetometry; fluorescence correlationspectroscopy; dynamic light scattering; and the like) and use ofnanostructures such as carbon nanotubes, enzyme linked immunosorbentassays, surface plasmon resonance, liquid chromatography, massspectrometry, circular proximity ligation assays, and the like.

Amelioration may include the use of a treatment system (e.g., UVradiation, IR radiation), as well as a substance, whose properties makeit suitable for amelioration. Amelioration of CSF or amelioratedCSF—which terms may be used interchangeably herein—refers to a treatedvolume of CSF in which one or more target compounds have been partially,mostly, or entirely removed. It will be appreciated that the termremoved, as used herein, can refer not only to spatially separating, asin taking away, but also effectively removing by sequestering,immobilizing, or transforming the molecule (e.g., by shape change,denaturing, digestion, isomerization, or post-translationalmodification) to make it less toxic, non-toxic or irrelevant.

The term, “ameliorating agent” generally refers to a material or processcapable of ameliorating a fluid, including enzymes, antibodies, orantibody fragments, nucleic acids, receptors, anti-bacterial,anti-viral, anti-DNA/RNA, protein/amino acid, carbohydrate, enzymes,isomerases, compounds with high-low biospecific binding affinity,aptamers, exosomes, ultraviolet light, temperature change, electricfield, molecular imprinted polymers, living cells, and the like.Additional details of amelioration are taught by PCT Application No.PCT/US20/27683, filed on Apr. 10, 2020, the disclosure of which isincorporated herein, in its entirety, by reference. In a similar manner,details for further treatments are taught by PCT Application No.PCT/US19/042880, filed Jul. 22, 2019, the disclosure of which isincorporated herein, in its entirety, by reference.

To control CSF flow within the body (e.g., through the ventricle),illustrative embodiments form a CSF circuit/channel (identified byreference number “10”) that manages fluid flow in a closed loop. FIG.1A, for example, shows one embodiment of such a CSF circuit 10. In thisexample, internal catheters 12 positioned in-vivo/interior to the bodyfluidly couple together via the subarachnoid space. To that end, a firstinternal catheter 12 fluidly couples a prescribed region of the brain(e.g., the ventricle) to a first port 16, which itself is configured andpositioned to be accessible by external components. In a correspondingmanner, a second catheter couples the lumbar region or the lower abdomenof the subarachnoid space with a second port 16 that, like the firstport 16, also is configured to be positioned and accessible by externalcomponents. The first and second ports 16 may be those conventionallyused for such purposes, such as a valved Luer-lock or removable needle.The first and second internal catheters 12 thus may be considered toform a fluid channel extending from the first port 16, to the ventricle,down the spine/subarachnoid space to the lumbar, and then to the secondport 16. These internal components, which may be referred to as“internal CSF circuit components,” are typically surgically implanted byskilled professionals in a hospital setting.

The CSF circuit 10 also has external components (referred to as“external CSF circuit components). To that end, the external CSF circuitcomponents include at least two fluid conduits 14. Specifically, theexternal CSF circuit components include a first external fluid conduit14, that couples with the first port 16 for access to the ventricle. Theother end of the first external conduit 14 is coupled with a managementsystem 19, which includes one or more CSF pumps (all pumps aregenerically identified in the figures as reference number “18”), one ormore user interface/displays 20, one or more drug pumps 18, and acontrol system/controller 22. The fluid external fluid conduit 14 may beimplemented as a catheter and thus, that term may be usedinterchangeably with the term “conduit” and be identified by the samereference number 14. Illustratively, this management system 19 issupported by a conventional support structure (e.g., a hospital pole 24in FIG. 1A). To close the CSF circuit 10, a second external catheter 14extends from that same CSF management system 19 and couples with thesecond port 16 and the management system 19. This management system 19and external catheters 14 therefore form the exterior part of a closedCSF circuit 10 for circulating the CSF and therapeutic material.

It should be noted that the CSF circuit 10 may have one or morecomponents between the first and second ports 16 and the respectiveremovable connections of the first and second external catheters 14. Forexample, the first port 16 may have an adapter that couples with thefirst external catheter 14, or another catheter with a flow sensor maycouple between such external catheter 14 and port 16. As such, thisstill may be considered a removable connection, albeit an indirect fluidconnection. There may be corresponding arrangements with the other endof the first external catheter 14, as well as corresponding ends of thesecond external catheter 14. Accordingly, the connection can be a directconnection or an indirect connection.

The first and second external catheters 12 and 14 preferably areconfigured to have removable connections/couplings with the managementsystem 19, as well as their respective ports 16. Examples of removablecouplings may include a screw-on fit, an interference fit, a snap-fit,or other known removable couplings known in the art. Accordingly, aremovable coupling or removable connection does not necessarily requirethat one forcibly break, cut, or otherwise permanently break the ports16 for such a connection or disconnection. Some embodiments, however,may enable a disconnection form the first and/or second ports 16 viabreaking or otherwise, but the first and/or second ports 16 shouldremain in-tact to receive another external catheter 14 (e.g., at the endof life of the removed external catheter 14).

FIG. 1B schematically shows more details of the first and/or secondexternal conduits/catheters 14. This figure shows an example of anexternal catheter 14 operating with other parts of the system. As shown,the system receives a drug reservoir 17 (e.g., a single-use syringe)configured to deliver a dose of therapeutic material (e.g., a drug) thatfluidly couples with the catheter 14 via a check valve 28 and T-port 19on the catheter 14. In addition, the catheter 14 is coupled with amechanical pump 18 and also preferably includes a sample port 23 withflow diverters 25 for diverting flow toward or away from a sample port23. The sample port 23 preferably has sample port flow sensors 23A totrack samples.

Some embodiments may be implemented as a simple catheter having a bodyforming a fluid-flow bore with removably couplable ends (or only oneremovably couplable end). Illustrative embodiments, however, addintelligence to make one or both of these external catheters 14 “smart”catheters, effectively creating a more intelligent flow system. Forexample, either one or both of the external catheters 14 can have aprocessor, ASIC, memory, EEPROM (discussed below), FPGAs, RFID, NFC, orother logic (generally identified as reference number “27”) configuredto collect, manage, control the device, and store information for thepurposes of security, patient monitoring, catheter usage, orcommunicating with the management system 19 to actively control fluiddynamics of the CSF circuit 10. Among other things, the managementsystem 19 may be configured to coordinate with an EEPROM 27 to controlCSF fluid flow as a function of the therapeutic material infusion flowadded to the CSF circuit 10 (discussed below) via the check valve 28 atthe output of the drug reservoir 17.

As shown in FIG. 1B, one embodiment of the external catheter 14 has thenoted electrically erasable programmable read-only memory, EEPROM 27,(or other logic/electronics) that can be implemented to accomplish avariety of functions. Among others, the EEPROM 27 can ensure that theCSF circuit 10 and its operation is customized/individualized to apatient, a treatment type, a specific disease, and/or a therapeuticmaterial. For example, in response to reading information stored in theEEPROM 27, the control system 22 may be configured to control fluid flowas a function of the therapeutic material.

Importantly, as a disposable device, the EEPROM 27 or other logic of theexternal catheter 14 can be configured to provide alerts, and/or produceor cause production of some indicia (e.g., a message, visual indication,audio indication, etc.) indicating that the external catheter 14 hasreached an end of its lifecycle, or indicating how much of its lifecycleremains. For example, an external surface of the catheter 14 may have atag that turns red when the EEPROM 27 and/or other logic 27 determinesthat the external catheter 14 has reached its full lifetime use. Forexample, the external catheter 14 may be considered to have a usagemeter, implemented as some logic or EEPROM 27, configured to track useof the CSF fluid conduit 14 to help ensure it is not used beyond itsrated lifetime. Moreover, the logic or EEPROM 27 can register with thecontrol system 22 to start use timers to reduce tampering or use beyonda lifetime.

Some embodiments have a printable circuit board (PCB) equipped with awireless interface (e.g., Bluetooth antenna) or a hardware connectionconfigured to communicate the pump 18 and/or control system 22. Theexternal catheter 14 can be configured to time out after a certainperiod, capture data, and communicate back and forth with the controlsystem 22 or other off-catheter or on-catheter apparatus to share systemspecifications and parameters. The intelligent flow catheter 14 can bedesigned with proprietary connections such that design of knockoffs orcartridges 26 (discussed below) can be prevented to ensure safety andefficacy of the CSF circuit 10 and accompanying processes.

In addition to the management logic, the external catheter(s) 14 alsomay have a set of one or more flow sensors and/or a set of one or morepressure sensors. Both of those flow sensors are shown generically atreference number 29, and may be located upstream or downstream fromtheir locations in FIG. 1B. For example, the left sensor(s) 29generically shown in FIG. 1B can be a flow sensor, pressure, or both aflow sensor and pressure. The same can be said for the right sensor(s)29 generically shown in FIG. 1B. They preferably are positioned betweenthe ports 16 on the body and the remaining components as shown.

Of course, the flow sensor(s) 29 may be configured to detect flowthrough the bore of the catheter body, while the pressure sensor(s) 29may be configured to detect pressure within the bore of the body. Amongother functions, the flow sensor(s) 29 may monitor flow rate of fluidthrough the conduit bore and/or total flow volume through the conduitbore.

The catheter 14 preferably is configured to have different hardnessvalues at different locations. Specifically, illustrative embodimentsmay use a mechanical pump 18, as shown and noted above. The pump 18 mayperiodically urge a compressive force along that portion of the catheter14 it contacts at its interface 18A with the catheter 14. The outlet ofthe pump 18 in this case may be the portion of the catheter 14 that isreceiving the output of a neighboring compressed catheter portion (e.g.,a portion that is adjacent to the compressed catheter portion(s). Tooperate efficiently, illustrative embodiments form the catheter 14 tohave a specially configured hardness at that location (e.g., 25-35 ShoreA). Diameter also is important for flow and thus, one skilled in the artshould determine appropriate diameters as a function of performance anddurometer/hardness. Preferably, the catheter portion that contacts thepump 18 is softer than the remainder of the catheter 14, although bothcould have the same hardness. Accordingly, the catheter preferably has avariable hardness along its length and may even have a variablediameter.

Alternative embodiments may provide an open-loop CSF fluid circuit 10.For example, the CSF fluid circuit 10 may have an open bath (not shown)to which fluid is added and then removed. The inventors expect theclosed-loop embodiment to deliver better results, however, than those ofthe open-loop CSF fluid circuit 10.

Illustrative embodiments are distributed to healthcare facilities and/orhospitals as one or more kits. For example, one more inclusive kit mayinclude the internal and external catheters 12 and 14. Another exemplarykit may include just the internal catheters 12 and the ports 16 (e.g.,for a hospital), while a second kit may have the external catheters 14and/or a single-use syringe. Other exemplary kits may include theexternal catheters 14 and other components, such as the managementsystem 19 and/or a CSF treatment cartridge 26. See below for variousembodiments of the CSF circuit 10 and exterior components that also maybe part of this kit.

Accordingly, when coupled, these pumps 18, valves (discussed below andall valves generally identified by reference number 28), internal andexternal catheters 14, and other components may be considered to form afluid conduit/channel that directs CSF to the desired locations in thebody. It should be noted that although specific locations and CSFcontaining compartments are discussed, those skilled in the art shouldrecognize that other compartments can be managed (e.g., the lateralventricles, the lumbar thecal sac, the third ventricle, the fourthventricle, and/or the cisterna magna). Rather than accessing theventricle and the lumbar thecal sac, both lateral ventricles could beaccessed with the kit. With both internal catheters 12 implanted, CSFmay be circulated between the two lateral ventricles, or a drug could bedelivered to both ventricles simultaneously.

In illustrative embodiments, the CSF management system 19 generallymanages fluid flow to target anatomy through the CSF circuit 10. To thatend, that management system 19 has at least one pump 18 that directsflow of the CSF, and at least one pump 18 that directs flow of atherapeutic material (e.g., a drug) though the CSF circuit 10 to desiredanatomy. Alternative embodiments may have more pumps 18 for thesefunctions, or combine pumps 18 for these functions. The managementsystem 19 also has a plurality of valves 28 to control flow, and thecontrol system 22, as noted, is configured to control the pumps 18 toselectively apply the drug-carrying CSF to desired local anatomy. FIG.1A also shows a user interface 20 that enables a clinician to controldrug and fluid parameters in the CSF circuit 10 (discussed below) viathe control system 22.

Some embodiments may use a monitoring process, such as real-timespectroscopy, to monitor drug concentrations in the CSF. In some ofthese embodiments, a spectrophotometric sensor may be placed in the CSFcircuit 10 to measure the localized concentration of a substance basedon its absorption at various wavelengths. For example, some embodimentsmay use a sensor constructed to measure a single wavelength or multiplewavelengths. The reading taken by the sensor may be relayed to thecontrol system 22, where it would then be stored or processed forvarious purposes. This signal could be processed for a number ofpurposes, such as to trigger the control system 22 to alter the fluidflow, flow direction, and/or frequencies of certain periodic flows ofbodily fluids (e.g., CSF) to provide a more localized and efficienttherapeutic application to a patient in real-time. It will beappreciated that the signal could also be stored or displayed such thatthe changes to flow, direction or frequencies of period flows could beadjust manually.

FIG. 1C shows a high level surgical flow process that may incorporatethe CSF circuit 10 of FIG. 1A in accordance with illustrativeembodiments of the invention. It should be noted that this process issubstantially simplified from a longer process that normally would beused to complete the surgical flow. Accordingly, this process may havemany additional steps that those skilled in the art likely would use. Inaddition, some of the steps may be performed in a different order thanthat shown, or at the same time. Those skilled in the art therefore canmodify the process as appropriate. Moreover, as noted above and below,many of the materials, devices, and structures noted are but one of awide variety of different materials and structures that may be used.Those skilled in the art can select the appropriate materials andstructures depending upon the application and other constraints.Accordingly, discussion of specific materials, devices, and structuresis not intended to limit all embodiments.

The process begins at step 100 by setting up the internal catheters 12inside the patient. To that end, step 100 accesses the ventricles andthecal sacs using standard catheters and techniques, thus providingaccess to the CSF. Step 102 then connects access catheters 12 toperitoneal catheters 12, which are tunneled subcutaneously to the lowerabdomen. The tunneled catheters 12 then are connected at step 104 to theports 16 implanted in the abdomen.

At this point, the process sets up an extracorporeal circulation set(i.e., the external catheters 14, or the “smart catheters” in someembodiments). To that end, step 106 may prime and connect theextracorporeal circulation set 14 to the subcutaneous access ports 16.Preferably, this step uses an extracorporeal circulation set, such asone provided by Endear Therapies, Inc. of Newburyport, Mass., and/or theexternal catheters 14 discussed above. The process continues to step110, which connects an infusion line or other external catheter 14 tothe management system 19, and then sets the target flow rate and time.At this point, setup is complete and treatment may begin (step 112).

The process then removes endogenous CSF from the ventricle. This CSF maythen be passed through a digestion region (e.g., through a cartridge 26having a specific digesting material), where certain target proteins inthe CSF are digested. For example, the cartridge 26 may have an innerplenum space 1830 of the cartridge 26 filled with a plurality of (e.g.,porous, chromatography resin) beads that have been compression packed.To prevent constituents from entering or escaping from the cartridge 26,a filter membrane may be disposed at the first end of the cartridge 26and a second filter membrane may be disposed at the second end of thecartridge 26. In some applications, the ameliorating agent may bedecorated on the beads 1835.

In some applications, the cartridge 26 may be compression packed with achromatography resin (e.g., agarose, epoxy methacrylate, amino resin,and the like) that has a protease covalently bonded (i.e. immobilized)to the three-dimensional resin matrix. The selected protease may beconfigured to degrade and/or removing target toxic biomolecules by wayof proteolytic degradation. The resin may be a porous structure having aparticle size commonly ranging between 75-300 micrometers and, dependingon the specific grade, a pore size commonly ranging between 300-1800 Å.Thus, at a high level, the cartridge 26 has ameliorating agent thatremoves and/or substantially mitigates the presence of toxic proteinsfrom the CSF.

This and similar embodiments may consider this to be an input for thedigesting enzyme. Any location providing access to the drug may beconsidered to be an input for the drug. At step 116, the treated CSFexits the digestion region and is returned via the CSF circuit 10 to thelumbar thecal sac. The process concludes at step 118, which stops thepump 18 when treatment is complete. The management system 19 then may bedisconnected and the ports 16 flushed.

In accordance with illustrative embodiments, the CSF circuit 10 isconfigured to improve the likelihood of the drug passing through theblood-brain barrier. To that end, the management system 19 enables theuser or logic to independently set both the flow rate of CSF circulation(e.g., between 0.05 ml/min and 2.0 ml/min, such as 0.5 ml/min) and thedosing rate of the drug (e.g., between 0.01 ml/min to 2.0 ml/min, suchas 0.02 ml/min). Preferably, these rates are different, although theycan be the same. In illustrative embodiments, the CSF circulation rateis controlled to be different from the natural CSF flow rate. Note thatthe natural CSF flow rate is the rate of CSF flow without interventionby outside equipment, such as the pumps 18 and other CSF circuitcomponents—even if it is within a range of typical non-interventionallycontrolled CSF flow rates. Thus, unless the context dictates otherwise,the non-natural CSF flow rate is the flow rate with such intervention.In other embodiments, the CSF flow rate is simply changed from its trulynatural flow rate—i.e., the rate at which the CSF flows withoutintervention.

Depending on a number of factors, the CSF flow rate may be greater thanthe rate of drug infusion, while in other embodiments, the CSF flow rateis less than rate of the drug infusion rate. Other embodiments may setthem to be equal. Those skilled in the art can select the appropriateflow rate based on a variety of factors, including the drug beingdelivered, the illness, patient profile, rated pressure of the CSFcircuit 10, etc.

The inventors recognized that varying the two rates in a coordinatedmanner enables more control of the drug dose as well as more control ofthe drug treatment time. Stated another way, these two independent flowrates enable setting of the dosing rate, which allows the user tooptimize drug concentration. At the same time, having the ability to setthe flow rate allows the user to control the rate of delivery (asopposed to relying upon natural CSF flow).

As noted in the example below, the inventors were surprised to discoverthat varying the rates in this manner enabled penetration of the drugacross the otherwise difficult to penetrate blood-brain barrier. Theselected CSF flow rate may be constant or variable. For example, the CSFflow rate may be set to a first rate for a first period of time, asecond rate for a second period of time, and a third rate for a thirdperiod of time. As such, various embodiments enable flow of the CSFwithin the CSF circuit 10 at two or more flow rates at two or moredifferent times. The drug delivery rate may be constant or variable in asimilar manner, but coordinated with the CSF flow rate to deliverpreferred results.

The inventors recognized that a wide variety of different CSF circuitconfigurations can accomplish the desired goals. FIG. 2 schematicallyshows a two pump CSF circuit 10 with the drug fed into the pump 18through a separate fluid line/catheter 12/14 in accordance withillustrative embodiments. In a corresponding manner, FIG. 3schematically shows a two pump CSF circuit 10 with drug introduceddirectly into fluid line.

In one embodiment, the CSF circuit 10 has two pumps 18, Pump 1 and Pump2, to enable a user to set flow rate and dosing rate independently. Tothat end, Pump 1 may be programmed to control the rate of CSFcirculation, while Pump 2 may be programmed to control the dosing rateof the drug to be delivered. Both pumps 18 could be programmed toachieve a desired delivery profile. Check valves 28 or other flowcontrol devices prevent backflow into either pump 18.

As show, the drug may be fed into the pump 18 through a separate fluidline/catheter (FIG. 2) and input to mix with the patient's CSF in theinternal catheter/tubing set 12 before being reintroduced to the body.Alternatively, the drug may also be pre-loaded into a cartridge 26 orother type of drug reservoir and connected directly into the fluidline/catheter 14 (FIG. 3). In this latter embodiment, the CSF mixes withthe drug as it flows through the cartridge 26 and tubing set 12/14. FIG.4A schematically shows another embodiment in which a flow control valve28 is used in place of Pump 2. In this embodiment, that flow controlvalve 28 preferably is programmed to control the dosing rate (i.e., therate of adding the drug to the CSF circuit 10 carrying the CSF.

FIG. 5 schematically shows a two-pump circuit 10 with a mixing chamber30 in accordance with illustrative embodiments. In particular, to ensurea homogeneous mixture of CSF and the drug being delivered, the notedmixing chamber 30 is added to both the two-pump circuit 10 (FIG. 5) andthe flow control valve 28 circuit (FIG. 6). The mixing chamber 30 cancontain a sensor that provides a readout of a drug's concentration inthe CSF, or the management system 19 could simply be programmed toproduce a specific drug concentration in the CSF.

In FIG. 5, the CSF-circulating pump 18 and the dosing pump 18 (via aninput) feed into the mixing chamber 30 at independent programmablerates. Upon entering the chamber, a small turbine mixes the fluids andthe homogeneous mixture is expelled and returned to the patient anatomy.The same concept applies to FIG. 6, but some in-line mixing occursbefore the fluids reach the mixing chamber 30.

Whether controlling dosing rate by a second pump 18 or by a flow controlvalve 28, CSF delivery may be manually programmed on aninterface/display 20 similar to FIGS. 7 and 8. Specifically, FIGS. 7 and8 schematically show two different user interfaces 20 in accordance withillustrative embodiments. Rather than requiring the user to input adosing rate, however, the user may specify a drug concentration and themanagement system 19 responsively may adjust the dosing rate accordinglyto achieve that concentration. The user can also input a maximum dosage.After this dosage was reached, the management system 19 wouldautomatically stop treatment. FIG. 8 shows one such interface 20 (e.g.,a graphical user interface or a manual interface).

It should be noted that the during actual processing, the CSF flow ratemay differ at different parts of the CSF circuit 10—total CSF flow ratein the CSF circuit 10 is not necessarily homogenous. For example, someparts of the CSF circuit 10 may be wider (e.g., certain humangeographies) and thus, may be slower than the average CSF circuit flowrate, while other portions may be narrower, causing a nozzle effect andincreasing the CSF flow rate at that point. Near the pump 18 (e.g., atthe pump outlet), however, the CSF flow rate can be controlled toprovide a desired rate across the entire CSF circuit 10, even if thatrate may deviate in local parts of the CSF circuit.

The discussion above relates to delivering a therapeutic material, suchas a drug, over a longer infusion period (e.g., 5 minutes, 10 minutes,30 minutes, 1-6 hours, days, etc.). FIG. 9 shows another embodiment thatlocalizes drug delivery at a target area of the brain using a bolus druginfusion. Specifically as known by those in the art, a dose of drug canbe delivered in a short time period (e.g., 10 seconds, 20 seconds, 60seconds), or over a longer period (i.e., gradual drug administration, asnoted above). The shorter drug delivery is known in the art as a “bolus”drug delivery.

Specifically, to optimize delivery, FIG. 9 alternates the flow directionof the pump 18. The pump 18 thus has programmable controls, via thecontrol system 22, for flow rate and frequency of these alternations.The flow rate and frequency preferably are programmed to achieve adesired delivery profile.

In a manner similar to the other process discussed above, the process ofFIG. 9 is substantially simplified from a longer process that normallywould be used to complete the localize drug delivery. Accordingly, thisprocess may have many additional steps that those skilled in the artlikely would use. In addition, some of the steps may be performed in adifferent order than that shown, or at the same time. Those skilled inthe art therefore can modify the process as appropriate. Moreover, asnoted above and below, many of the materials, devices, and structuresnoted are but one of a wide variety of different materials andstructures that may be used. Those skilled in the art can select theappropriate materials and structures depending upon the application andother constraints. Accordingly, discussion of specific materials,devices, and structures is not intended to limit all embodiments.

FIG. 9 therefore delivers a drug intrathecally using positivedisplacement at a desired flow rate. It may incorporate the componentsdiscussed above, as well as principles discussed for other embodiments,such as that discussed above with regard to FIG. 2. The process of FIG.9 begins at step 900 by adding the drug in a bolus dose to the CSFcircuit 10, and/or administering a tag for imaging to the drug. In thelatter example, its position can then be tracked using standard imagingtechniques to determine when the drug has reached the target anatomy.Alternative embodiments add the drug to the CSF without administering atag. Such steps may use other techniques to ensure the drug is localizedat the desired target anatomy.

Step 902 sets the desired flow rate, direction, timing, and otherparameters for the CSF circuit 10 to accomplish the bolus application.For example, specific computer program code on a tangible medium withinthe control system 22 may cooperate with other components of the CSFcircuit 10 to control addition of the therapeutic material, localize thetherapeutic material, or both. Next, after step 904 verifies theposition of the drug at a target anatomy, step 906 controls the pump 18to maintain the drug at that target location. Among other ways, step 906may control the pump(s) 18 to oscillate at a desired flow rate andfrequency to contain the drug at that prescribed or desired anatomicallocation for a pre-set period of time.

After the bolus reaches the target anatomy, the pump 18, which can beprogrammable and/or have logic, can reverse CSF flow; specifically, thepump 18 can alternate quickly between pushing and pulling flow of theCSF so that the bolus of drug is localized to the target anatomy in thebrain (or another target anatomy). In other words, the higherconcentration of drug in a portion of the CSF can moved back and forthover the target region. Other embodiments can simply slow down the CSFflow rate to ensure a longer drug application to the target. Either way,these embodiments preferably “soak” the target with the drug, providinga higher quality drug administration. As a result, despite using less ofthe drug than would be administered by prior art systems, thisembodiment still administers a desired amount of the drug to the targetby this localizing technique, consequently minimizing toxicity and drugcosts (step 908).

It should be noted that “reaching” the target anatomy may be defined bythe user or other entity within the control system 22. For example, theportion of CSF in the CSF circuit 10 having the higher concentration ofdrug (from the bolus) may be considered to have reached the targetanatomy when some identifiable portion of it (e.g., the highestconcentration, or an interior point within the spread of the drug in theCSF) may be within a prescribed distance upstream of the target, or aprescribed distance downstream of the target. Some embodiments mayrequire the defined portion of CSF with the high drug concentration toactually be at or in contact with that target region. Other embodimentsmay consider the drug to have “reached” the target simply by calculatingthe time it should take to reach that area, using artificialintelligence/machine learning, and/or through empirical studies.

Illustrative embodiments can be implemented in a number of differentmanners with catheters 12/14, pumps 18, valves 28, etc. similar to thosediscussed above (including the noted external catheters 14). FIGS. 10-14show several exemplary implementations. In the embodiment shown in FIG.10, the CSF circuit 10 has four pinch valves 28 on tubing (i.e.,external catheters 14), enabling fluid oscillation between opposing flowdirections. To flow from lumbar to ventricle (FIG. 10), pinch valves 1and 2 are opened while pinch valves 3 and 4 are closed. Conversely, toswitch flow direction from ventricle to lumbar (FIG. 11), pinch valves 1and 2 are closed while pinch valves 3 and 4 are opened. Controlling thepinch valves 28 in this manner enables flow direction oscillation. Thefrequency at which the pinch valves 28 switched between open and closedmay be set by the user as could the flow rate of the pump 18 (e.g., viathe control system 22). Alternative embodiments may pre-program suchparameters into the management system 19.

In fact, the same pinch valve 28 configuration (FIG. 12) may be used tocreate a pulsatile flow pattern. For example, when flowing from lumbarto ventricle, pinch valves 3 and 4 remain closed, while pinch valves 1and 2 are pulsed (i.e., periodically switched between open and closed)at a frequency set by the user.

The ability to set the frequency at which the pinch valves 28 open andclose enables a range of pulsatile effects to be implemented. Forexample, rather than rapidly switching between open and closed pinchvalves 28, the valves 28 can remain closed long enough to build up a setpressure in the fluid line. Shortly after opening the pinch valves 28, abolus of the drug can be released as a result of the pressure build-up.

Flow direction oscillation and a pulsatile flow pattern could also beproduced using a bidirectional pump 18 instead of using pinch valves 28(e.g., FIG. 13A and FIG. 13B). The pump 18 can be programmed to switchflow directions at a frequency set by the user. While flowing in onedirection, the pump 18 can be programmed to pulse by starting andstopping at a frequency also set by the user. Those skilled in the artmay use other techniques to provide bidirectional flow.

In addition to those noted above, some embodiments may set thefrequency, flow rate, and other parameters as a function of therequirements and structure of the anatomy and devices used in thetreatment (e.g., in the CSF circuit 10). Among others, thoserequirements may include the diameter of the catheters in the CSFcircuit 10, physical properties of the drug, the interaction of the drugat the localized region, the properties of the localized region, andother requirements and parameters relevant to the treatment. Thoseskilled in the art may select appropriate parameters as a function ofthe requisite properties.

FIG. 14 schematically shows another system interface 20 configured inaccordance with illustrative embodiments. Specifically, whethercontrolling delivery parameters by pinch valve, a bidirectional pump 18,or other means, the delivery profile can be controlled manually with aninterface 20, such as the interface 20 shown in FIG. 14, and/or adelivery profile loaded onto the management system 19. As with the otherinterfaces, this interface 20 may be a fixed control panel, or agraphical user interface on a display device.

FIG. 15 shows a process of manually programming drug delivery of a bolusin accordance with illustrative embodiments. In a manner similar to theother process discussed above, this process is substantially simplifiedfrom a longer process that normally would be used to complete thelocalize drug delivery. Accordingly, this process may have manyadditional steps that those skilled in the art likely would use. Inaddition, some of the steps may be performed in a different order thanthat shown, or at the same time. Those skilled in the art therefore canmodify the process as appropriate. Moreover, as noted above and below,many of the materials, devices, and structures noted are but one of awide variety of different materials and structures that may be used.Those skilled in the art can select the appropriate materials andstructures depending upon the application and other constraints.Accordingly, discussion of specific materials, devices, and structuresis not intended to limit all embodiments.

The process begins at step 1500, which sets the flow direction. Threeoptions include lumbar to ventricle (1502A), ventricle to lumbar (step1502B), or oscillating between flow directions (step 1502C). Next, theprocess sets the flow rate at steps 1504A or 1504B, and sets thefrequency of the pulse (step 1506A) or oscillation frequency (step1506B). Alternative embodiments can be programmed using artificialintelligence algorithms or other program logic.

Example 1: Administration of Methotrexate to a Sheep Using IllustrativeEmbodiments

The inventors administered methotrexate to sheep using illustrativeembodiments. An outline of the study is depicted by FIGS. 16A-16C. Asheep used for this experiment received the CSF circuit 10 ofillustrative embodiments. Circulation was started at the same time thatmethotrexate was infused. Methotrexate was infused at a gradual rate of2 mLs over 2 minutes and then recirculation from lumbar to ventricle wasstarted at a rate of 0.2 mLs/min. Circulation continued after druginfusion was stopped for four more hours. At zero to three hours, thecirculation rate was at 0.1 mL/min and from four to six hours,circulation was at 0.3 mL/min. The dose of methotrexate infused was 12mg. Drug concentration was measured with LC/MS (liquid chromatographywith the mass analysis capabilities of mass spectrometry) in the CSF,spinal cord, and multiple brain regions.

FIG. 16B schematically shows the results. CSF levels of methotrexatewere analyzed over time. Drug levels were found to be very high in thelumbar region where the drug was infused and a decline over time wasmeasured except for an increase at 5 hours and then a subsequentdecline. CSF levels of methotrexate were very low in the ventricularsamples initially, but with time, increased at 4 and 5 hours, beforedeclining to a similar level as the lumbar samples.

FIG. 16C shows how samples from twelve regions of the brain werehomogenized and analyzed for methotrexate levels and measured as ug/mL/gof tissue. The x-axis of this graph is drug levels. All areas of thebrain and spinal cord had good levels of methotrexate. It will beappreciated that methotrexate that is administered typically subdural inthe thigh typically does not cross the blood-brain barrier and would notbe found in appreciable levels in brain and spinal cord as a result.

Example 2: Administration of Antisense Oligonucleotide to a Sheep UsingIllustrative Embodiments

The inventors administered an antisense oligonucleotide (ASO) forHuntington's disease to sheep using illustrative embodiments. An outlineof the study is depicted in FIGS. 17A-C. Each sheep used for thisexperiment received the CSF circuit 10 of illustrative embodiments.Circulation was started at the same time that ASO was infused. ASO wasinfused at a rate of 2 mLs over 2 min. The dose of ASO infused was 30mg. Circulation continued after drug infusion was stopped for four morehours. At zero to four hours, the circulation rate was at 0.2 mL/min.For unidirectional flow, the direction of the flow was lumbar toventricle me for the entire 4 h. For the bidirectional flow, the first 1h of flow was lumbar to ventricle, then the direction of flow wasreversed to ventricle to lumbar for 10 min, then switched repeatedly for10 min intervals for the remainder of the 4 h. All sheep in the studywere necropsied after 48 h and tissues were collected to assay druglevels.

The assay for detection of the ASO is depicted in FIG. 17B. Sandwichhybridization ELISA (Enzyme-Linked-immuno-absorption-Assay)quantification used to measure the concentration of CAG repeats intissue, CSF, and blood samples. Probes comprised of a sequencecomplementary to the analyte. Capture DNA probe conjugated to biotinlabel and applied to a streptavidin-coated microliter plate. DetectionDNA probe with digoxigenin label was used. To detect digoxigenin label,anti-digoxigenin (anti-Dig) peroxidase (POD) is reacted with substrateTMB for the signal measurement by an absorption change with a platereader.

FIG. 17C schematically shows the results. Samples from seventeen regionsof the brain were homogenized and analyzed for ASO levels and measuredas ug/g of tissue. The x-axis of this graph is drug levels. Most areasof the brain and spinal cord had good levels of ASO. It will beappreciated that the ASO if administered orally, subdurally, orintravenously typically does not cross the blood-brain barrier and wouldnot be found in appreciable levels in brain and spinal cord as a result.

Of course, those skilled in the art should recognize that the aboveexamples are two of many examples that may be used with illustrativeembodiments.

Accordingly, illustrative embodiments enable a clinician to moreeffectively treat various diseases by targeting drug delivery via CSF inthe subarachnoid space.

Various embodiments of the invention may be implemented at least in partin any conventional computer programming language. For example, someembodiments may be implemented in a procedural programming language(e.g., “C”), or in an object oriented programming language (e.g.,“C++”). Other embodiments of the invention may be implemented as apre-configured, stand-along hardware element and/or as preprogrammedhardware elements (e.g., application specific integrated circuits,FPGAs, and digital signal processors), or other related components.

In an alternative embodiment, the disclosed apparatus and methods (e.g.,see the various flow charts described above) may be implemented as acomputer program product for use with a computer system. Suchimplementation may include a series of computer instructions fixedeither on a tangible, non-transitory medium, such as a computer readablemedium (e.g., a diskette, CD-ROM, ROM, or fixed disk). The series ofcomputer instructions can embody all or part of the functionalitypreviously described herein with respect to the system.

Those skilled in the art should appreciate that such computerinstructions can be written in a number of programming languages for usewith many computer architectures or operating systems. Furthermore, suchinstructions may be stored in any memory device, such as semiconductor,magnetic, optical or other memory devices, and may be transmitted usingany communications technology, such as optical, infrared, microwave, orother transmission technologies.

Among other ways, such a computer program product may be distributed asa removable medium with accompanying printed or electronic documentation(e.g., shrink wrapped software), preloaded with a computer system (e.g.,on system ROM or fixed disk), or distributed from a server or electronicbulletin board over the network (e.g., the Internet or World Wide Web).In fact, some embodiments may be implemented in a software-as-a-servicemodel (“SAAS”) or cloud computing model. Of course, some embodiments ofthe invention may be implemented as a combination of both software(e.g., a computer program product) and hardware. Still other embodimentsof the invention are implemented as entirely hardware, or entirelysoftware.

The embodiments of the invention described above are intended to bemerely exemplary; numerous variations and modifications will be apparentto those skilled in the art. Such variations and modifications areintended to be within the scope of the present invention as defined byany of the appended claims.

What is claimed is:
 1. A CSF management method for use with a patienthaving a body with CSF having a natural flow rate, the methodcomprising: forming a closed loop CSF circuit between two points on thebody, the CSF circuit comprising a therapeutic inlet to receive atherapeutic material, the CSF circuit also comprising a pump having apump outlet to direct CSF along the CSF circuit; controlling the pump todirect CSF proximate to the pump outlet at a CSF rate, the CSF ratebeing different from the natural flow rate; adding the therapeuticmaterial to the CSF via the therapeutic inlet, the therapeutic materialbeing added to the CSF circuit at a therapeutic rate, the CSF rate beingdifferent than the therapeutic rate.
 2. The method as defined by claim 1wherein the CSF rate is a constant rate.
 3. The method as defined byclaim 1 wherein the CSF rate varies over time.
 4. The method as definedby claim 1 wherein the CSF circuit is configured so that the CSFsimultaneously flows at different rates at two different locations ofthe CSF circuit.
 5. The method as defined by claim 1 wherein the CSFcircuit accesses one or more CSF-containing compartments within patientanatomy, including one or more of the lateral ventricles, the lumbarthecal sac, the third ventricle, the fourth ventricle, and the cisternamagna.
 6. The method as defined by claim 1 wherein the CSF rate isgreater than the therapeutic rate.
 7. The method as defined by claim 1wherein the CSF circuit comprises a port into the patient, the CSFcircuit further comprising a fluid channel removably coupled with theport and the pump.
 8. The method as defined by claim 7 wherein the fluidchannel comprises a flow sensor, a pressure sensor, or both a flowsensor and a pressure sensor.
 9. The method as defined by claim 8wherein the fluid channel comprises a controller in communication withthe pump, the controller being configured to track the total number ofuses of the fluid channel.
 10. The method as defined by claim 1 furthercomprising receiving user input via a graphical user interface, the userinput being used to determine the CSF rate.
 11. A CSF management systemfor use with a patient having a body with CSF having a natural flowrate, the system comprising: a catheter configured to at least in partform a closed loop CSF circuit between two points on the body; atherapeutic inlet to the CSF circuit configured to receive a therapeuticmaterial at a therapeutic rate; a pump configured to direct CSF carryingthe therapeutic material along the CSF circuit; and a controlleroperatively coupled with the pump, the controller configured to controlthe pump to direct CSF at a CSF rate, the CSF rate being different fromthe natural flow rate, the controller configured to set the CSF rate tobe different from the therapeutic rate.
 12. The system as defined byclaim 22 wherein the CSF rate is a constant rate.
 13. The system asdefined by claim 22 wherein the CSF rate varies over time.
 14. Thesystem as defined by claim 22 wherein the CSF circuit is configured sothat the CSF simultaneously flows at different rates at two differentlocations of the CSF circuit.
 15. The system as defined by claim 22wherein the CSF circuit accesses one or more CSF-containing compartmentswithin patient anatomy, including one or more of the lateral ventricles,the lumbar thecal sac, the third ventricle, the fourth ventricle, andthe cisterna magna.
 16. The system as defined by claim 22 wherein theCSF rate is greater than the therapeutic rate.
 17. The system as definedby claim 22 wherein the two points on the body comprise ports thatpermit access to the interior of the patient.
 18. The system as definedby claim 22 wherein the catheter comprises a flow sensor, a pressuresensor, or both a flow sensor and a pressure sensor.
 19. The system asdefined by claim 18 wherein the catheter comprises a controller incommunication with the pump, the controller being configured to trackand limit use of the catheter.
 20. The system as defined by claim 22wherein the therapeutic inlet comprises a syringe or a fluid bag. 21.They system as defined by claim 22 further comprising a sample port influid communication with the catheter, the sample port having aremovable port configure to sample fluid through the catheter.
 22. Acomputer program product for use on a computer system for managing aclosed loop CSF circuit between two points on a patient's body havingCSF with a natural flow rate, the computer program product comprising atangible, non-transient computer usable medium having computer readableprogram code thereon, the computer readable program code comprising:program code for controlling a pump having a pump outlet to direct CSFfrom the pump outlet at a CSF rate, the CSF rate being different fromthe natural flow rate; program code for adding the therapeutic materialto the CSF via a therapeutic inlet into the CSF circuit, the therapeuticmaterial being added to the CSF circuit at a therapeutic rate; andprogram code for controlling the CSF rate to be different than thetherapeutic rate.
 23. The computer program product as defined by claim22 wherein the CSF rate is a constant rate.
 24. The computer programproduct as defined by claim 22 wherein the CSF rate varies over time.25. The computer program product as defined by claim 22 wherein the CSFcircuit is configured so that the CSF simultaneously flows at differentrates at two different locations of the CSF circuit.
 26. The computerprogram product as defined by claim 22 wherein the CSF circuit accessesone or more CSF-containing compartments within patient anatomy,including one or more of the lateral ventricles, the lumbar thecal sac,the third ventricle, the fourth ventricle, and the cisterna magna. 27.The computer program product as defined by claim 22 wherein the CSF rateis greater than the therapeutic rate.
 28. The computer program productas defined by claim 22 wherein the two points on the body comprise portsthat permit access to the interior of the patient.
 29. The computerprogram product as defined by claim 22 wherein the CSF circuit comprisesan external catheter, the computer program product further comprisingprogram code to track and limit use of the catheter.